The neocortex is the most complex neural system in the mammalian brain and is responsible for mediating the highest forms of perception and cognition. Central to current views of the physiology of higher cortical function is the concept of synaptic plasticity, or use-dependent modifications of synaptic efficacy. When such activity proceeds in a focused and coherent manner the process is associated with normal behavior, healthy cortical development, and normal learning and memory formation. When the process becomes deranged and goes unchecked, neuropathology results, leading to mental disorder and abnormal behavior. The specific disease entity describing a given abnormality will depend on the etiology and the location of the derangement. Understanding normal cortical function and dysfunction must begin at the level of the local neuronal circuit. While most studies of excitotoxicity concentrate on excitatory mechanisms, we will continue to focus on the system which opposes and thereby regulates excitability, namely GABAergic inhibition. The primary goal of this proposal is to examine the dynamics of excitatory drive onto rat neocortical inhibitory interneurons. We have two hypotheses regarding cortical interneurons mediating fast inhibition: 1) they possess few functional NMDA receptors, and 2) they communicate via electrotonic transmission. We further postulate that modulating the activity of AMPA/kainate glutamate receptors or electrotonic synapses will alter the excitability of interneurons, and thereby GABA-mediated inhibitory currents in pyramidal cells. In vitro experiments will be carried out to test these hypotheses with regard to the following issues: 1) Defining the nature of evoked and spontaneous glutamatergic excitation in interneurons, 2) Examining how NMDA and non-NMDA modulation affect interneuron activity, 3) Specifying how non-NMDA modulators affect fast GABAA inhibition recruitment (and the overall effect on the relative excitation-inhibition balance), 4) Gathering physiological evidence for electrotonic transmission in interneurons, and 5) Testing whether modulation of electrotonic coupling alters fast inhibitory strength in pyramidal cells.